Compositions and methods for treating female sexual response

ABSTRACT

The present invention relates to compositions, articles of manufacture, methods of preparation thereof, methods of use thereof, etc., for enhancement of sexual pleasure, conditions, disorders, and diseases related to reproductive physiology and systems, especially of mammalian females. For instance, the present invention relates to all aspects of modulating the female sexual response, including female sexual dysfunction, such as female sexual arousal disorders (FSAD), orgasmic disorders, and sexual pain disorders, and enhancing female sexual pleasure and satisfaction of the female sexual experience. Accordingly, the present invention relates to compositions comprising botanical extracts, active agents, etc., which are useful to treat or affect any of the aforementioned conditions. For example, the present invention relates to a composition, preferably for topical or local use, which comprises one or more of the following ingredients, including, but not limited to, borage seed oil,  Angelica pubescens  root and other  angelica  species,  Coleus forskohlii  extract, vinpocetine, ferulic acid, magnesium, ascorbyl palmitate, capric/caprylic triglyceride, silica, and equivalents thereof.

[0001] This application claims the benefit of U.S. ProvisionalApplication 60/214,472, filed Jun. 27, 2000, which is herebyincorporated by reference in its entirety.

DESCRIPTION OF THE INVENTION

[0002] While increased understanding of the pathophysiology of maleerectile dysfunction progressed rapidly in the past decade and led tonew therapeutic modalities, little has been done to address similarissues in women. Accordingly, the present invention relates to allaspects of modulating the female sexual response, including femalesexual dysfunction, such as female sexual arousal disorders (FSAD),orgasmic disorders, and sexual pain disorders, and enhancing the femalesexual experience. In particular, the present invention relates tocompositions, articles of manufacture, methods of preparation thereof,methods of use thereof, etc., for conditions, disorders, and diseasesrelated to female reproductive physiology systems, especially thoseinvolved in the female sexual response.

[0003] Compositions comprising botanical extracts, active agents, etc.,can be produced and used in accordance with the present invention thatare useful to treat or affect the female sexual response. For example,the present invention relates to compositions, preferably for topical orlocal use, which comprise one or more of the following ingredients,including, but not limited to, borage seed oil and other sources ofgamma linolenic acid (GLA), Angelica pubescens root, Coleus forskohliiextract, vinpocetine, and other naturally-occuring cyclic adenosinemonophosphate (cAMP) and cyclic guanine monophosphate (cGMP)phosphodiesterase (PDE) inhibitors and equivalents thereof. Thecompositions can produce one or more of the following pharmacologicaleffects, including, but not limited to, increases in localized nitricoxide, cAMP production and/or elevation, cGMP production and/orelevation, prostaglandin E₁ production, inhibition of prostaglandin E₁breakdown, calcium channel antagonism, phosphodiesterase inhibition,anti-oxidation, vasodilation, smooth muscle relaxation, etc.

[0004] A useful composition in accordance with the present invention cancomprise borage seed oil or other borage plant parts, preferably fromBorago officianalis. The borage plant (e.g., leaves, roots, and seeds)comprises a complex mixture of defined and undefined constituents,including, e.g., acetic acid; alkaloids; allantoin; amabiline;arabinose; ascorbic-acid; beta-carotene; bornesitol; calcium; choline;cobalt; dhurrin; fat; fiber; galactose; gamma linolenic acid; glucoseplant; intermedine; lycopsamine; magnesium; malic acid; mucilage;niacin; phosphorus potassium; protein; pyrrolizidines; resin;riboflavin; rosmarinic acid; silicic acid; sodium; supinine; supinineviridiflorate; thiamin and zinc. A preferred bioactive ingredient ofBorage is gamma linolenic acid (GLA) having a molecular weight of 278.GLA is a polyunsaturated fatty acid (PUFA) belonging to the group offatty acids called omega-6 or N-6 fatty acids because of the presence ofa double bond between the 6th and 7th carbon. GLA is found predominantlyin the seed of the Borage plant, but is also found in evening primroseseed oil and other botanical and natural sources.

[0005] Borage seed oil can be prepared by any suitable method,preferably methods which extract GLA and other bioactive agents, such ascold pressure extraction, screw pressure extraction, solvent extraction,supercritical fluid extraction, etc. A borage seed oil can comprise anyamount of GLA, preferably, e.g., by weight, at least about 10%, 15%,20%, 25%, 30%, etc. The oil preferably is free of compounds which aretoxic, or deleterious to mammals, such as alkaloids, pyrrolizidine, etc.

[0006] Borage seed oil can be present in a composition of the presentinvention in any effective amount, e.g., 1-100%, 10-95%, 20-95%, 30-95%,50-95%, 70-90%, 60-90%, 80%, 81%, 82%, 83%, 84%, 84.25%, 85%, 86%, 87%,etc., w/w (i.e., weight of ingredient/weight of total composition).

[0007] In addition to borage seed oil, other sources of GLA can beutilized, including, e.g., purified or isolated GLA, botanical extracts,such as evening primrose oil (e.g., Oenothera biennis and Oenotheralamarckiana), black currant oil, spirulina, oils from the seeds of theRibes family, etc.

[0008] Borage seed oil has a variety of beneficial effects andactivities, including, but not limited to, e.g., inhibiting plateletaggregation, lowering blood pressure, anti-inflammatory activity,vasodilation, prostaglandin promoting activity, PGE₁ promoting activity(see, below), promoting circulating hormones, causing smooth musclerelaxation, etc. Borage seed oil can be included in a composition of thepresent invention in amounts which are effective to achieve one or moreof the aforementioned effects.

[0009] A composition of the present invention can also compriseAngelica, such as Angelica archangelica, Angelica sinensis, Angelicasylvestris, Angelica officinalis, archangel, European angelica, gardenangelica, Angelica acutiloba, preferably Angelica pubescens which isalso known as Du Huo or Du Huo Radix. Angelica root is preferred, butother parts of the plants can be used as well. Angelica contains a wideand complex variety of different constituents, of a defined andundefined nature. Preferred bioactive compounds are flavinoids, flavonesand coumarins, preferably, osthole or7-methoxy-8-(3-methylpent-2-enyl)coumarin, and alpha-angelicalactone.Other coumarins, include, e.g., meranzin hydrate, nodakentin,marmesinin, columbianadin, columbianetin, bergapten, heramandiol,6-alkylcoumarins, angelol-type coumarins, byak-angelicin, ferulin,oxypeucedanin, umbelliprenin, imperatorin, neobyakangelicin,prenylcourmarins, glabralactone, anpubesol, angelical, angelin,furanocourmins, and derivatives thereof. Other bioactive agents include,e.g., linoleic acid, osthenol, falcarindiol, numerous flavinoids andflavones, 11(S),16(R)-dihydroxyoctadeca-9Z,17-diene-12,14-diyn-1-yl-acetate,xanthotoxin, umbelliferone, ferulic acid, magnesium, and derivativesthereof.

[0010]Angelica possesses a number of pharmacological activities,including, but not limited to smooth muscle relaxant activity,phosphodiesterase inhibition, calcium antagonist activity, cycloxygenaseand 5-lipoxygenase inhibition (e.g, Liu et al., Pharm. Bio.,36(3):207-216, 1998), etc. Coumarins, and osthole in particular, havebeen identified to display activities such as, inhibition of plateletaggregation, inhibition of smooth muscle contraction, smooth musclerelaxation (e.g., Che-Ming et al., Naunyn-Schmiedeberg's Arch.Pharmacol., 349:202-208, 1994), inhibition of calcium flux, cyclicnucleotide (such as cGMP and cAMP) phosphodiesterase inhibition,increase in cAMP and cGMP levels, anti-proliferative, anti-inflammatory(Yuh-Fung et al., Planta Medica, 61(1):2-8, 1995), enhancement of theincrease of cAMP and cGMP induced by forskolin, vasorelaxation,neurotransmitter receptor binding, such as GABA, 5HT-1A, D-2, and D-1receptors (Jyh-Fei et al., Proceedings of the National Science CouncilRepublic of China, Part B, Life Sci., 19(3):151-158, 1995), etc.Alpha-angelicalactone also possesses various activities, including,e.g., calcium antagonism. See, e.g., Entman et al., J. Clin. Invest.,48:229-234, 1969. Ferulic acid, another component of Angelica root alsohas been shown to scavenge oxygen free radicals and increaseintracellular cAMP and cGMP. See, e.g. Zheng RL, Zhang H., Free RadicBiol Med., 22(4):581-586,1997. Preferred activities of Angelica arecyclic nucleotide phosphodiesterase inhibition, calcium antagonism,oxygen free radical scavenging, smooth muscle modulation, as eithervasorelaxant or vasodilatory.

[0011] A composition of the present invention can comprise any effectiveamount of Angelica, preferably Angelic pubescens root, e.g., 0.1-99%,0.1-80%, 0.1-50%, 0.5-8%, 1%, 2%, 3%, 4%, 5%, etc. w/w.

[0012] In another embodiment of the present invention, a composition canfurther comprise Coleus forskohlii, preferably from its tuber or roots.The plant is a member of the Labiatae family and grows as a perennial.It is native to India, Nepal, Sri Lanka, and Thailand. See, e.g., TheWealth of India, Vol. 11, C.S.I.R., India, 1950, Page 308. Coleusforskohlii comprises a diverse and complex mixture of compounds, e.g.,diterpenes, and derivatives thereot. A preferred bioactive diterpenecompound is forskolin and related diterpenes.

[0013]Coleus forskohlii can be utilized in any form which is effective,including, but not limited to dry powders, grounds, emulsions, creams,extracts, and other conventional formulations. Extracts can be preparedroutinely, e.g. by contacting the plant parts with a suitable solvent toextract a diterpene or other compound from the material (e.g., see, U.S.Pat. No. 4,118,508, JP 11292777, and JP 6133731 for extractionprocesses). Any amount of Coleus which is effective can be utilized incompositions of the present invention, e.g., at least about 0.1-99%,0.1-80%, 0.1-50%, 0.5-8%, 1%, 2%, 3%, 4%, 5%, etc. w/w of an 80%extract.

[0014]Coleus forskohlii, particularly forskolin and related diterpenes,have a number of biological activities, including, smooth musclerelaxation, adenylate cyclase stimulation, elevation of levels of cAMP,anti-inflammatory, ant-spasmodic, etc. Since forskolin and relatedditerpenes stimulate adenylate cyclase, resulting in the production ofthe second messenger cAMP, any biological process mediated by cAMP cantherefore be stimulated by administration of Coleus forskohlii.

[0015] Compositions of the present invention can also comprisevinpocetine (eburnamenine-14-carboxylic acid ethylester) and derivativesthereof. Vinpocetine is a naturally-occurring product found, e.g., invinca minor (periwinkle). It can be extracted from natural sources, suchas vinca, or produced synthetically. Various derivatives of vinpocetinecan be utilized, including salts. For methods of synthesis ofvinpocetine and derivatives, e.g., U.S. Pat. No. 4,035,370; Szabo etal., Arch. Pharm., 316:629-638; Tungler et al., J. Mol. Catalysis,108:45-152, 1996; U.S. Pat. No. 4,749,707 (e.g., citrate and phosphatesalts). Vinpocetine and its derivatives have various activities andeffects, including, e.g., phosphodiesterase inhibition, selective PDEtype I inhibition, vasodilation activity, smooth muscle relaxation,increases in levels of cAMP and/or cGMP. etc.

[0016] Any amount of vinpocetine which is effective can be utilized incompositions of the present invention, e.g., at least about 0.1-99%,0.1-80%, 0.1-50%, 0.5-8%, 1%, 2%, 3%, 4%, 5%, etc.

[0017] In addition to the above-mentioned botanical extracts, or as analternative thereof, a composition of the present invention can compriseany agent which possesses one of more of the biological activitiesassociated with said botanical extracts.

[0018] For example, the present invention also relates to agents having“PGE₁ promoting activity.” As mentioned, one of the major constituentsof borage seed oil is GLA. GLA is a precursor of prostaglandin E1(PGE₁), a potent biological effector molecule. PGE₁ has manyphysiological effects. While not wishing to be bound to any theory, itis believed that at least some of the beneficial effects produced byborage seed oil is mediated by its delivery of a precursor to the PGE₁metabolic pathway, thereby stimulating production of PGE₁. Thus, anycompound, mixtures thereof, compositions, botanicals, etc. whichcomprise a PGE₁ or a PGE₁ precursor can be characterized as having “PGE₁promoting activity,” e.g., causing the production of PGE₁, or possessingPGE₁ activity.

[0019] Another useful class of agents in accordance with the presentinvention are those which elevate levels of cyclic nucleotides, such ascAMP and cGMP, e.g., by inhibiting phosphodiesterases which hydrolyzethe cyclic nucleotides, by stimulating adenylate cyclase, or receptorscoupled thereto, by acting on G-proteins, etc. In accordance with thepresent invention, any amount of elevation or increase of cyclicnucleotide which is effective to elicit a desired result, such astreating FSD, enhancing sexual arousal, etc. Amounts of increase ascompared to normal can be at least 5%, 10%, 50%, 75%, 90%, 1-fold,2-fold, 5-fold, 10-fold, 20-fold, etc. These increases can be sudden,transient over a few minutes, localized, etc., as long as the desiredeffect is achieved, e.g., modulating the female sexual response.

[0020] Elevation of levels of cyclic nucleotides can be accomplished bycyclic nucleotide phosphodiesterase (PDE) inhibition. There are a numberof different cyclic nucleotide phosphodiesterase isoenzymes, includingtypes I, II, III, IV, V, VI, and VII. See, e.g., Nicolson et al., 1991.PDE inhibitors can be non-selective (e.g., theophylline or caffeine), orselective for one or more PDE isoenzymes. Selective inhibitors, include,I (vinpocetine), III (milrinone, amrinone, pimobendan, cilostamide,enoximone, peroximone, vesnarinone), IV (rolipram, R02-1724), and V(zaprinast, dipyridamole). Other useful PDE inhibitors include compoundsdisclosed in U.S. Pat. No. 5,958,926.

[0021] In addition to elevating levels of cAMP through inhibition ofPDEs (e.g., utilizing Angelica pubsescens root extract and other speciesof Angelica) cAMP levels can be elevated by directly stimulatingadenyate cyclase and causing synthesis of cAMP, e.g., using Coleusforskohlii, and derivatives thereof. Useful forskolin derivatives, andtheir synthesis, are disclosed in, e.g., EP 222,413, U.S. Pat. Nos.5,789,439, 5,350,864, 5,206,241, 5,177,207, 5,145,855, 5,093,336,4,999,351, and 4,134,986.

[0022] Compositions can be administered in any form by any effectiveroute, including, e.g., oral, parenteral, enteral, intraperitoneal,topical, local, dermal, transdermal, ophthalmic, nasally, nasopharyngealabsorption, local, topical, non-oral, aerosal, inhalation, subcutaneous,intramuscular, buccal, sublingual, rectal, vaginal, intra-arterial,rapid infusion, intravenously, long-release implants, etc.

[0023] In preferred embodiments of the invention, compositions areadministered to the external female genitalia and/or vaginally, e.g., asa vaginal cream, foam, gel, jelly, liquid, emulsion, solution,suspension, cream, spray, powder, suppository, tablet, device, etc. Forexample, a composition can be preferably applied to the female externalgenitalia, such as the mons pubis, labia majora and minora, hymen,clitoris, prepuce of the clitoris, vestibule of the vagina, and/orvestibular glands. The external genitalia is also called the vulva orpudendum. Compositions can also be applied to the internal wall of thevagina, e.g., to the adventia, muscularis, mucosa, and rugae.

[0024] A composition of the present invention can also be administeredby or in the form of a device, such as a cartridge, diaphragm, femalemechanical barrier-type device, feminine cap (e.g., U.S. Pat. Nos.4,858,624, 4,989,618, and 5,207,232), film, intrauterine barrier-typedevice, sponge, tampon, osmotic drug delivery device (e.g., U.S. Pat.Nos. 5,795,591, 4,475,916, and 4,093,708), ring, or sheath. Such devicescan carry the composition in any effective manner, e.g., a device can beimpregnated or coated with the composition, or fitted with a carrierelement, such as a film (e.g., U.S. Pat. No. 5,529,782), or polymericmaterial, etc., that contains composition. The device can then beinserted into the vagina where delivery is effected. See, e.g., U.S.Pat. No. 4,317,447. A device can be a sponge-like structure, such as apolymeric sponge tampon, which contains a composition of the presentinvention. See, e.g., U.S. Pat. No. 4,393,871. Such a device can beinserted into the vagina prior to intercourse. The device can also bereusable. In the case of devices, it can be advantageous to formulatethe composition with compounds, such as water-soluble polymers ordissolvable materials, which disintegrate in the vaginal fluids, therebyreleasing the active agents. Any suitable polymer can be used, e.g., asdescribed in U.S. Pat Nos. 5,840,685 5,393,528, 5,084,277, 4,835,138,4,323,548, and 4,322,399.

[0025] A composition of the present invention can also be administeredby a male condom, e.g., by applying the composition to the condom priorto insertion into the vagina, e.g., in combination with otherlubricants, or, as a dry or wet film or coating on the exterior of thecondom surface. See, e.g., U.S. Pat. No. 5,954,054.

[0026] In general, any delivery means, including devices, polymers,etc., that are used to deliver agents vaginally can be utilized inaccordance with the present invention, such as means for deliveringantiviral agents, bacteriocides, contraceptives, hormones, spermicides,virucides, lubricants, etc.

[0027] Compositions of the present invention can further comprise otheractive agents, including, e.g., contraceptive agents, spermicidalagents, such as, e.g., nonoxynol-9, octoxynol, menfegol, benzalkoniumchloride, peroxygen compounds or hydrogen peroxide (e.g., U.S. Pat. No.5,778,886), bacteriocides, germicides, antiviral agents, virucides,vasodilators, agents which increase vaginal lubrication (e.g., hydriodicacid syrup as disclosed in U.S. Pat. No. 5,470,588), etc.

[0028] In addition, compositions of the present invention can furthercomprise any agent which enhances the sexual response and/or treatdiseases and conditions related to sexual dysfunction. Such agentsinclude, e.g., apomorphine (e.g., U.S. Pat. No. 5,945,117), nitric oxidereleasing compounds (e.g., U.S. Pat. No. 5,877,216), ginkgo (e.g., U.S.Pat. No. 5,897,864), hydriodic acid (U.S. Pat. No. 5,470,588), agentsdisclosed in U.S. Pat. No. 4,521,421.

[0029] The compositions of the present invention can further compriseany pharmaceutically acceptable carrier. By the phrase,“pharmaceutically acceptable carrier,” it is meant any excipient,solvent, vehicle, inert ingredient, etc., which is formulated with theactive ingredients of a pharmaceutical composition, such as the standardagents described, e.g., in Remington's Pharmaceutical Sciences,Eighteenth Edition, Mack Publishing Company, 1990. Examples of suitablecarriers are well known in the art and can include, but are not limitedto, water, phosphate buffered saline solutions, phosphate bufferedsaline containing Polysorb 80, emulsions such as oil/water emulsion andvarious type of wetting agents, salt solutions, alcohols, gum arabic,vegetable oils, benzyl alcohols, aqueous vehicles, water-misciblevehicles, nonaqueous vehicles (e.g., corn oil, cottonseed oil, peanutoil, sesame oil, ethyl oleate, isopropyl myristate, and benzylbenzoate), etc. Carriers also include, e.g., milk, sugar, certain typesof clay, silica, gelatin, stearic acid or salts thereof, magnesium,magnesium stearate and other forms or salts of magnesium, or calciumstearate, talc, vegetable fats or oils, gums, glycols, propylene glycol,buffers, antimicrobial agents, preservatives, flavor, fragrance andcolor additives, gelatin, carbohydrates such as lactose, amylose orstarch, talc, silicic acid, viscous paraffin, perfume oil, fatty acidmonoglycerides and diglycerides, pentaerythritol fatty acid esters,hydroxy methylcellulose and the like. Other additives include, e.g.,antioxidants and preservatives, coloring, flavoring and diluting agents,emulsifying and suspending agents, such as acacia, agar, alginic acid,sodium alginate, bentonite, carbomer, carrageenan,carboxymethylcellulose, cellulose, cholesterol, fatty acids,triglycerides and esters of fatty acids, fatty alcohols, gelatin,hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, methylcellulose, octoxynol 9, oleyl alcohol, povidone,propylene glycol monostearate, sodium lauryl sulfate, sorbitan esters,stearyl alcohol, tragacanth, xanthan gum, and derivatives thereof,solvents, transdermal enhancers (ethanol, propylene glycol, water,sodium oleate, leucinic acid, oleic acid, capric acid, sodium caprate,capric/caprylic triglyceride, silica, lauric acid, sodium laurate,neodecanoic acid, dodecyl-amine,. cetryl lactate, myristyl lactate,lauryl lactate, methyl laurate, phenyl ethanol, hexa-methylenelauramide, urea and derivatives, dodecyl N, N-dimethylamino acetate,hydroxyethyl lactamide, phyophatidylcholine, sefsol-318 (a medium chainglyceride), isopropyl myristate, isopropyl palmitate, palmitic acid,several surfactants, including poly-oxyethylene (10) lauryl ether (Brij361 R), diethyleneglycol lauryl ether (PEG-2-L), laurocapram (Azone;1,1-dodecylazacycloheptan-2-one), acetonitrile, 1-decanol,2-pyrrolidone, N-methylpyrrolidone, N-ethyl-1-pyrrolidone,1-Methyl-2-pyrrolidone, 1-lauryl-2-pyrrolidone, sucrose monooleate,dimethylsulfoxide (DMSO) about 80% concentration required,decylmethylsulfoxide (n) enhances primarily polar or ionic molecules(soluble in ethanol), acetone, polyethylene glycol 100-400 MW,dimethylacetamide, dimethylformamide, dimethylisosorbide, sodiumbicarbonate, various N₇₋₁₆-alkanes, mentane, menthone, menthol,terpinene, D-terpinene, dipen-tene, N-nonalool and limonene, skinpenetration enhancers (e.g., lecithin), and miscellaneous ingredientssuch as microcrystalline cellulose, citric acid, dextrin, dextrose,liquid glucose, lactic acid, lactose, magnesium chloride, potassiummetaphosphate, starch, and the like.

[0030] As mentioned, compositions of the present invention can compriseone or more of the following ingredients, e.g., borage seed oil,Angelica pubescens root, Coleus forskohlii extract, magnesium and itssalts, ferulic acid, vinpocetine, and equivalents thereof, in anybinary, trinary, etc., combination. Such ingredients can be present insynergistic amounts. Examples of topical compositions, include, e.g.,binary combinations, such as an effective amounts of borage seed oil,and Angelica pubescens root; effective amounts of borage seed oil, andColeus forskohlii extract; effective amounts of Angelica pubescens root,and Coleus forskohlii extract; and quarternary combinations, such aseffective amounts of borage seed oil, Angelica pubescens root, Coleusforskohlii extract, and vinpocetine. Such compositions can furthercomprise pharmaceutically-acceptable excipients, skin- and mucosalpenetration enhancers, etc. In preferred embodiments, included asexcipients are, e.g., de-ionized water (e.g, about 0.5-50%, preferably5%, concentration), Span 80 (sorbitan monooleate (e.g., 0.2-20%,preferably 2%, concentration), lecithin (e.g., egg or soyphosphatidylcholine (e.g., e.g., 0.2-20%, preferably 2%, concentration),lavendar for body oils by Flavor and Fragrance Specialties (0.05-1,25%,preferably 0.25%), Blackberry Musk for body oils by Flavor and FragranceSpecialties (0.1-2.5%, preferably 0.5%) or other flavors and fragrances,glycerin (e.g., 2-10% w/w), saccharin or other sweetening agents, andmonsodium Gaunosine Mono Phosphate (flavor enhancer), silica, ferulicacid and other forms of ferulate, magnesium sulfate and other forms ofmagnesium, vitamine E acetate and other forms of tocopherol, andascorbyl palmitate and other forms of ascorbic acid along with otheranti-oxidants and stability enhancers. Ingredients, and amounts ofingredients, can be adjusted such that the compositions possess minimalirritation to the female reproductive organs. Ingredients can also beincluded that enhance the cosmetic appeal (e.g., enhancing the smell,feel, etc.) of the compositions, but which are inert as far as enhancingthe sexual response, e.g., enhancing the smell, feel, etc., of acomposition.

[0031] A quarternary topical composition can comprise, e.g., a) borageseed oil and/or evening primrose oil is 10-99% w/w of said composition;b) Angelica pubescens is 0.001-99% w/w of said composition, c) Coleusforskohlii is 0.001-8% w/w of said composition, and d) vinpocetine is0.001-8% w/w of said composition. This composition can further comprise,e.g., e) magnesium 0.001-90%, f) ferulic acid 0.001-10%.

[0032] The present invention also relates to methods of using any of thementioned compositions, e.g., for treating or affecting diseases andconditions associated with sexual function, especially associated withthe female reproductive system, such as for treating sexual dysfunction,facilitating sexual arousal, enhancing or improving sexual response, orenhancing or improving sexual pleasure, comprising administering aneffective amount of a composition in accordance with the presentinvention. By “sexual functioning,” it is meant any activity associatedwith the genitalia, such as sexual intercourse. The methods are usefulto treat various types of female sexual dysfunction (FSD), such asfemale sexual arousal disorder (FSAD), desire disorders, orgasmicdisorders, and sexual pain disorders. Premenopausal and post-menopausalwomen can be treated.

[0033] The stages of female sexual activity include excitement(arousal), plateau, and orgasm. The arousal response is a physiologicaland psychological process involving, e.g., muscle relaxation,vasocongestion, vasodilation, and muscular contraction. The clitoriswhich contains a rich supply of sensory endings becomes erect as aresult of vasocongestion. During intercourse, the vaginal epitheliumbecomes highly congested and secretes a mucus-like lubricant which is anexudate. See, e.g., Human Physiology, Vander et al., Fifth Edition,McGraw-hill Publishing Company, 1990, e.g., Page 628; Current MedicalDiagnosis, Tierney et al., Eds., 1997, e.g., Pages 962-965; U.S. Pat.No. 5,958,926, especially Column 7-9. Compositions of the presentinvention can particularly facilitate and/or enhance arousal and orgasm,e.g., by enhancing associated vasocongestion and vasodilation andsensory input.

[0034] Sexual arousal disorders, e.g., inability to become aroused orinability to attain or maintain sufficient sexual excitement, femaleimpotence, vaginismus, frigidity, disorders of sexual desire, e.g.,absence of libido, decreased or loss of sensation, etc. can be treatedor affected in accordance with the present invention. In additiori,sexual pain disorders, such as painful intercourse, or dyspareunia, canbe treated. The latter can be caused by a number of factors, including,e.g., endometriosis, vaginismus, insufficient lubrication of the vagina,etc. FSAD can be manifested by a patient as a lack of subjectiveexcitement, a lack of genital lubrication or swelling, or anothersomatic responses. Disorders of arousal include, but are not limited to,lack or diminished vaginal lubrication, decreased clitoral and labialsensation, decreased clitoral and labial engorgement, lack of vaginalsmooth muscle relaxation, and disorders involving hormonal status.Compositions of the present invention can treat any of the mentionedconditions associated with female sexual dysfunction.

[0035] In addition, the compositions are useful for enhancing orimproving sexual response and/or enhancing or improving sexual pleasureand sensation. By the terms, “enhance” or “improve,” it is generallymeant that administration of a composition increases the subject'ssatisfaction with the sexual activity as compared to the activity whenin the absence of the composition. This includes, e.g., enhancement ofvaginal wetness, warmth, engorgement, sensitivity, sensation, tingling,arousal, orgasm, quicker to arousal, quicker to orgasm, and enhancementof any of the above-mentioned conditions (e.g., clitoral and labialsensation or vaginal smooth muscle relaxation), etc. Any amount ofincrease in satisfaction can be achieved, including, e.g., 1%, 5%, 10%,50%, 100%, 2-fold, etc. Satisfaction can be determined by any suitablemethod, e.g., a survey or questionnaire in which a user is asked toassess, after using a composition of the present invention, changes inthe genital area and sexual pleasure.

[0036] By the term “administering,” it is meant that a composition isdelivered to the subject in such a way that it can achieve the desiredpurpose, e.g., treating a condition or disease associated with sexualfunction. As mentioned, such composition can be administered by anyeffective route, preferably vaginally, such as topically or locally.Compositions of the present invention can be administered to anysuitable subject, preferably human females, but also to females of otherspecies, such as apes, monkeys, chimpanzees, pets, such as dogs, cats,rats, hamsters, and mice, horses, pigs, cows, sheep, and other domesticanimals, and males of any species.

[0037] In addition to females having any of the aforementionedconditions, suitable female subjects, include, e.g., females havingillnesses that interfere with sexual arousal, such as diabetes mellitus,hypothyroidism, pelvic disorders, neurological disorders (e.g., multiplesclerosis), muscular disorders (e.g., muscular dystrophy), andpsychological disorders (guilt, anxiety, depression, fatigue, orinterpersonal conflicts), conditions that lead to failure of thevasocongestion response, vaginal dryness, anorgasmic females,intermittently orgasmic females, orgasmic females desiring greatersexual response, sexual-related failures associated with age, neurosis,females having sexual desire disorders, orgasmic dysfunction,drug-induced sexual dysfunction (e.g., associated with oralcontraceptives, anti-hypertensives, tranquilizers, SSRIantidepressants), hypoactive sexual desire (HSD), postmenopausal women,etc.

[0038] Administration of compositions of the present invention canalleviate, improve, or ameliorate any of the mentioned conditions. Inaddition, sexual response can be improved, e.g., decreasing foreplay(e.g., the time usually required for a subject to reach arousal),decreasing latency time between orgasms, decreasing the time to reachorgasm, and facilitating orgasm and multiple orgasm.

[0039] An effective amount of a composition is administered to a targetsubject. Effective amounts are such amounts that are useful to achievethe desired effect, preferably a beneficial, pleasurable or therapeuticeffect as described above. Such amounts can be determined routinely,e.g., by administering different dosages to subjects and surveying orquestioning such subjects after sexual activity about their preferencesand the effectiveness of the treatment. Amounts can be selected based onvarious factors, including the age, health, gender, and weight of thesubject.

EXAMPLES Example 1 Preparation of Base Oil

[0040] Freshly milled Angelica pubescens root was mixed in a 1:1weight/weight ratio (other ratios, as described above can be used, e.g.,0.8:1) with borage seed oil (e.g., containing 20-26% GLA content,depending on the specific source). Lavender for Body Oils and BlackberryMusk for Body Oils (obtained from Flavor and Fragrance Specialties) wereeach added at a concentration of 10 mg/ml. (Optionally, in some cases,primrose oil (e.g., 9% GLA content) was added to the base oil for afinal concentration of 1% primrose oil.) This mixture was stirredrapidly in a water-jacketed blender, and heated at 80° C. for a 3-hourperiod. The resulting finely-divided solid/oil mixture was cooled toroom temperature, filtered once through a 20-micron filter, and thenrefiltered through a 5-micron filter. The base oil mixture was bright.gold-colored with a mild odor of Angelica pubescens.

Example 2 Preparation of a Gel Composition for Topical Application

[0041] A composition was formulated comprising 70% of the base oilproduced according to Example 1. To this oil, Coleus forskohli(containing about 80% forskolin) was added to the base oil for a finalconcentration of 10 mg/ml base oil. Vinpocetine was to this at a finalconcentration of 10 mg/ml base oil.

[0042] The following further ingredients were added to the mixture, butare optional ingredients: magnesium sulfate (USP or FCC) at aconcentration of 40 mg/ml, capric/caprylic triglyceride (at about 25%w/w) to enhance permeation, ferulic acid from Angelica species at 1-20mg/ml, acorbyl palmitate to stabilize oil and retard oxidation,alpha-tocopherol and tocopherol acetate to stabilize oil and retardoxidation, soy lecithin granular USP or FCC) at a concentration of 1-50mg/ml of base oil, span 80 (sorbitan monooleate) at 1-10 mg/ml of baseoil, fumed silica (at about 4% w/w) to form a gel version of the oil,and saccharin. Propylene glycol can be added to increase lubricity, butwere not used in the case examples below.

[0043] The above mixture was heated and rapidly stirred in a water bathset at 70° C. for 30 minutes. After cooling to room temperature, themixture was filtered through once through a 20-micron filter, and thenrefiltered through a 5-micron filter. The resulting mixture iscentrifuged at 11,000 rpm for 5 minutes, and the oil portion iscollected. To further clarify the product, the mixture is filtered,under vacuum, through a 5-micron filter, and then placed in an amberglass screw top container and stored at room temperature.

Example 3 Preparation of an Oil Composition for Topical application

[0044] To prepare an oil for topical application, a composition isformulated in accordance with Example 2, but fumed silica is omitted,and optionally capric/caprylic acid, as well.

Case Examples Case Example 1

[0045] A multi-parous perimenopausal forty-two year old woman in amonogamous relationship with self-described complaints of difficultywith sexual arousal and difficulty with vaginal lubrication during sexvolunteered to use a composition produced according to Example 2. Withthe consent of her partner, she applied approximately 0.6 mil to herclitoris and labial areas during foreplay. The woman indicated apleasurable gradual warming sensation to the areas of application. Shereported that within five minutes of application, the warming hadreached a plateau and that her clitoral sensation was increased. Alsoher labia began to feel plump or swollen (aroused). She reported nodifficulties with lubricating and claimed that sex was much morepleasurable and that her vaginal sensation had increased. Neither hernor her partner reported any adverse effects. Her partner reported thatshe was clearly more sexually aroused than usual and that her vagina waswarmer than usual. Both partners indicated they would try more samplesif provided.

Case Example 2

[0046] A multi-parous post-menopausal fifty-three year old woman in amonogamous relationship with self-described complaints of decreasedclitoral and vaginal sensation volunteered to use a composition producedaccording to Example 2. With her partner's consent, she appliedapproximately 0.6 ml to her clitoral and labial areas and applied theremainder of the vial (0.4 ml) to her partner's penis during foreplay.The couple reported approximately ten minutes of foreplay. The womanclaimed feeling a gradual warming and heightened sensation of herclitoris and vagina within about five minutes after application. Herpartner also noticed a slight warming effect of his penis. The couplereported engaging in intercourse after about ten minutes of foreplay.The woman claimed that the composition significantly improved hersensations during intercourse and overall had increased her sexualsatisfaction. Her partner claimed that from the looks (expressions) onher face, she seemed to enjoy his thrusting more than usual. Neitherpartner reported any adverse effects. Both partners indicated they wouldregularly use the composition if provided with more samples.

Case Example 3

[0047] A monoparous thirty-four year old woman in a monogamousrelationship who described herself as sexually normal volunteered to usea composition produced according to Example 2. With the consent of herpartner, she applied approximately 0.7 ml to her clitoral and labialareas during foreplay. After about five minutes she reported apleasurable and gradually building warming sensation that reached aplateau of intensity in about ten minutes. She claimed that thecomposition made it easier to reach orgasm and made it more intense thanusual. She also claimed its pleasurable effects lasted for aboutforty-five minutes. She reported the composition significantlyheightened her sexual experience and would use it regularly if she couldget more samples. Neither partner reported any adverse reactions.

Case Example 4

[0048] A thirty-eight year old woman volunteered to use 0.5 ml of acomposition produced according to Example 2. Using a standardizedconsumer testing results questionnaire, she reported the followinginformation: a) That sensation and sensitivity in her genital areaseemed to be more than usual. b) That it was pleasurable and satisfying.c) That she first noticed the change in sensation in about five minutes.c) That the change in sensation lasted approximately one hour. d) Thatshe experienced enhanced warmth, tingling and arousal. e) That afterusing the product, intercourse was more pleasurable and satisfying thannormal. f) That her vaginal lubrication seemed to be the same as always.g) That her ability to achieve orgasm was unchanged. h) That the productenhanced her sexual experience and would like to continue using it. i)That she would purchase the product and use it on special occasions andwhen she needed a boost. j) That she did not experience any unpleasantor unwanted effects.

Case Example 5

[0049] A thirty year old woman volunteered to use 0.5 ml of acomposition produced according to Example 2. Using a standardizedconsumer testing results questionnaire, she reported the followinginformation: a) That sensation and sensitivity in her genital areaseemed to be more than usual. b) That it was pleasurable and satisfying.c) That she first noticed the change in sensation in about two to threeminutes. c) That the change in sensation lasted approximately fortyminutes. d) That she experienced enhanced wetness, warmth, enhancedfullness (engorgement) and enhanced sensitivity. e) That after using theproduct, intercourse was more pleasurable and satisfying than normal. f)That her vaginal lubrication seemed to be more than usual. g) That herability to achieve orgasm was unchanged. h) That the product enhancedher sexual experience and would like to continue using it. i) That shewould purchase the product and use it routinely. j) That she did notexperience any unpleasant or unwanted effects.

Case Example 6

[0050] A forty-four year old woman volunteered to use 0.5 ml of acomposition produced according to Example 2. Using a standardizedconsumer testing results questionnaire, she reported the followinginformation: a) That sensation and sensitivity in her genital areaseemed to be more than usual. b) That it was pleasurable and satisfying.c) That she first noticed the change in sensation in four to fiveminutes. c) That the change in sensation lasted more than one hour. d)That she experienced enhanced wetness, warmth, tingling, sensation,orgasm and quicker to orgasm. e) That after using the product,intercourse was more pleasurable and satisfying than normal. f) That hervaginal lubrication seemed to be more than usual. g) That her ability toachieve orgasm was easier to achieve. h) That the product enhanced hersexual experience and would like to continue using it. i) That she wouldpurchase the product and use it on special occasions and when she neededa boost. j) That she did not experience any unpleasant or unwantedeffects.

Case Example 7

[0051] A twenty-three year old woman volunteered to use 1 ml of acomposition produced according to Example 2. Using a standardizedconsumer testing results questionnaire, she reported the followinginformation: a) That sensation and sensitivity in her genital areaseemed to be more than usual. b) That it was pleasurable and satisfying.c) That she first noticed the change in sensation in a few minutes. c)That the change in sensation lasted approximately thirty minutes. d)That she experienced enhanced warmth, tingling, arousal, sensation,orgasm and quicker to orgasm. e) That after using the product,intercourse was more pleasurable and satisfying than normal. f) That shedid not notice a change in her vaginal lubrication, but her partner did.g) That her ability to achieve orgasm was easier to achieve. h) That theproduct enhanced her sexual experience and would like to continue usingit. i) That she would purchase the product and use it when she needed aboost. j) That she did not experience any unpleasant or unwanted effectsexcept for slight irritation.

Case Example 8

[0052] A fifty-four year old woman volunteered to use 1 ml of acomposition produced according to Example 2. Using a standardizedconsumer testing results questionnaire, she reported the followinginformation: a) That sensation and sensitivity in her genital areaseemed to be more than usual. b) That it was pleasurable and satisfying.c) That she first noticed the change in sensation in two minutes. c)That the change in sensation lasted approximately forty-five minutes. d)That she experienced enhanced wetness, warmth, tingling, sensation, andarousal. e) That after using the product, intercourse was morepleasurable and satisfying than normal. f) That her vaginal lubricationseemed to be more than normal. g) That her ability to achieve orgasm waseasier to achieve. h) That the product enhanced her sexual experienceand would like to continue using it. i) That she would purchase theproduct and use it routinely. j) That she experienced some slightburning and soreness. She added that her partner said it made him moresensitive and he had a better climax.

Case Example 9

[0053] A fifty year old woman volunteered to use 0.5 ml of a compositionproduced according to Example 2. Using a standardized consumer testingresults questionnaire, she reported the following information: a) Thatsensation and sensitivity in her genital area seemed to be more thanusual. b) That it was pleasurable and satisfying. c) That she firstnoticed the change in sensation in about five minutes. c) That she didnot pay attention to how long the change in sensation lasted. d) Thatshe experienced enhanced wetness, warmth, tingling, sensation andenhanced orgasm. e) That after using the product, intercourse was morepleasurable and satisfying than normal. f) That she did not notice achange in her her vaginal lubrication, but her partner noticed.increased lubrication. g) That her ability to achieve orgasm wasunchanged. h) That the product enhanced her sexual experience and wouldlike to continue using it. i) That she would purchase the product anduse it when she needed a boost. j) That she did not experience anyunpleasant or unwanted effects. She also commented that she could notuse it regularly because her partner enjoys oral sex.

Case Example 10

[0054] A forty-three year old woman volunteered to use 1 ml of acomposition produced according to Example 2. Using a standardizedconsumer testing results questionnaire, she reported the followinginformation: a) That sensation and sensitivity in her genital areaseemed to be more than usual. b) That it was pleasurable and satisfying.c) That she first noticed the change in sensation in about ten minutes.c) That the change in sensation lasted approximately one hour. d) Thatshe experienced enhanced wetness, warmth, tingling, sensation, arousal,orgasm and quicker to orgasm. e) That after using the product,intercourse was more pleasurable and satisfying than normal. f) That hervaginal lubrication seemed to be more than usual. g) That her orgasm waseasier to achieve. h) That the product enhanced her sexual experienceand would like to continue using it. i) That she would purchase theproduct and use it on special occasions. j) That she did not experienceany unpleasant or unwanted effects other than some minor burning andsoreness.

Case Example 11

[0055] A thirty-eight year old woman volunteered to use 1 ml of acomposition produced according to Example 2. Using a standardizedconsumer testing results questionnaire, she reported the followinginformation: a) That sensation and sensitivity in her genital areaseemed to be more than usual. b) That it was pleasurable and satisfying.c) That she first noticed the change in sensation in about ten minutes.c) That the change in sensation lasted approximately two hours. d) Thatshe experienced enhanced warmth, tingling and arousal. e) That afterusing the product, intercourse was more pleasurable and satisfying thannormal. f) That her vaginal lubrication seemed to be the same as always.g) That her ability to achieve orgasm was unchanged. h) That the productenhanced her sexual experience and would like to continue using it. i)That she would purchase the product and use it on special occasions. j)That she experienced some minor burning, but did not feel any productimprovements were necessary.

Case Example 12

[0056] A twenty-four year old woman volunteered to use 1 ml of acomposition produced according to Example 2. Using a standardizedconsumer testing results questionnaire, she reported the followinginformation: a) That sensation and sensitivity in her genital areaseemed to be more than usual. b) That it was pleasurable and satisfying.c) That she first noticed the change in sensation in about two minutes.c) That the change in sensation lasted approximately forty-five minutes.d) That she experienced enhanced warmth and tingling. e) That afterusing the product, intercourse was more pleasurable and satisfying thannormal. f) That her vaginal lubrication seemed to be the same as always.g) That her ability to achieve orgasm was unchanged. h) That the productenhanced her sexual experience and would like to continue using it. i)That she would purchase the product and use it on special occasions andwhen she needed a boost. j) That she did not experience any unpleasantor unwanted effects other than some minor burning.

Case Example 13

[0057] A forty-seven year old woman volunteered to use 1 ml of acomposition produced according to Example 2. Using a standardizedconsumer testing results questionnaire, she reported the followinginformation: a) That sensation and sensitivity in her genital areaseemed to be more than usual. b) That it was pleasurable and satisfying.c) That she first noticed the change in sensation in about threeminutes. c) That the change in sensation lasted approximately thirtyminutes. d) That she experienced enhanced warmth, tingling andsensation. e) That after using the product, intercourse was morepleasurable and satisfying than normal. f) That her vaginal lubricationseemed to be the same as always. g) That her ability to achieve orgasmwas unchanged. h) That the product enhanced her sexual experience andwould like to continue using it. i) That she would purchase the productand use it routinely. j) That she did not experience any unpleasant orunwanted effects.

Case Example 14

[0058] A thirty year old woman volunteered to use 1 ml of a compositionproduced according to Example 2. Using a standardized consumer testingresults questionnaire, she reported the following information: a) Thatsensation and sensitivity in her genital area seemed to be more thanusual. b) That it was pleasurable and satisfying. c) That she firstnoticed the change in sensation in about four to five minutes. c) Thatthe change in sensation lasted approximately one and one-half hours. d)That she experienced enhanced wetness, warmth, tingling, fullness(engorgement), sensation, arousal, orgasm, quicker to arousal andquicker to orgasm. e) That after using the product, intercourse was morepleasurable and satisfying than normal. f) That her vaginal lubricationseemed to be more than usual. g) That her ability to achieve orgasm wasunchanged. h) That the product enhanced her sexual experience and wouldlike to continue using it. i) That she would purchase the product anduse it on special occasions. j) That she did not experience anyunpleasant or unwanted effects.

Case Example 15

[0059] A twenty-five year old woman volunteered to use 0.5 ml of acomposition produced according to Example 2. Using a standardizedconsumer testing results questionnaire, she reported the followinginformation: a) That sensation and sensitivity in her genital areaseemed to be more than usual. b) That it was pleasurable and satisfying.c) That she first noticed the change in sensation in about five minutes.c) That the change in sensation lasted approximately one hour. d) Thatshe experienced enhanced warmth, tingling, sensation, arousal, orgasmand quicker to orgasm. e) That after using the product, intercourse wasmore pleasurable and satisfying than normal. f) That her vaginallubrication seemed to be the same as always. g) That it was easier forher to achieve orgasm. h) That the product enhanced her sexualexperience and would like to continue using it. i) That she wouldpurchase the product and use it on special occasions and when she neededa boost. j) That she did not experience any unpleasant or unwantedeffects.

[0060] Without further elaboration, it is believed that one skilled inthe art can, using the preceding description, utilize the presentinvention to its fullest extent. The following preferred specificembodiments are, therefore, to be construed as merely illustrative, andnot limitative of the remainder of the disclosure in any way whatsoever.

[0061] In the foregoing and in the following examples, all temperaturesare set forth uncorrected in degrees Celsius; and, unless otherwiseindicated, all parts and percentages are by weight.

[0062] The entire disclosure of all applications, patents andpublications, cited above, and of corresponding U.S. ProvisionalApplication Ser. No. 60/214,472, filed Jun. 27, 2000, is herebyincorporated by reference.

1. A topical composition comprising: a) an effective amount of borageseed oil, and b) an effective amount of Angelica pubescens root.
 2. Atopical composition of claim 1, further comprising: c) an effectiveamount of Coleus forskohlii extract.
 3. A topical composition of claim1, further comprising: c) an effective amount of vinpocetine.
 4. Atopical composition of claim 1, further comprising: c) an effectiveamount of Coleus forskohlii extract, and d) an effective amount ofvinpocetine.
 5. A topical composition of claim 4, wherein a) borage seedoil is 10-99% w/w of said composition, b) Angelica pubescens rootextract is 0.001-99% w/w of said composition, c) Coleus forskohlii is0.001-8% w/w of said composition, and d) vinpocetine is 0.001-8% w/w ofsaid composition.
 6. A topical composition comprising: a) an effectiveamount of borage seed oil, and b) an effective amount of Coleusforskohlii extract.
 7. (Cancelled)
 8. A topical composition comprising:a) an effective amount of Angelica pubescens root, and b) an effectiveamount of Coleus forskohlii extract.
 9. (Cancelled)
 10. (Cancelled) 11.(Cancelled)
 12. (Cancelled)
 13. A topical composition of claim 4,further comprising a pharmaceutically acceptable topical excipient. 14.A topical composition of claim 13, wherein said excipient is one or moreof: magnesium and its salts, ferulic acid, capric/caprylic triglyceride,silica, vitamin E, vitamin E acetate or salts thereof, ascorbylpalmitate or salts thereof, saccharin, fragrances, and flavors.
 15. Atopical composition of claim 13, further comprising 2-10 wt % deionizeddistilled water, 0.5-5 wt % sorbitan monooleate, 0.5-5 wt % lecithin and0.25-2 wt % of flavor and/or fragrance enhancers.
 16. A method offacilitating female sexual arousal, female sexual response or heightenedfemale genital sensation, comprising administering an effective amountof a composition of claim
 1. 17. A method of treating female sexualarousal disorder, female orgasmic disorder, or female sexual paindisorder comprising administering an effective amount of a compositionof claim
 12. 18. A method of treating female sexual dysfunction,comprising administering an effective amount of a composition ofclaim
 1. 19. (Cancelled)
 20. (Cancelled)
 21. A topical compositioncomprising: effective amounts of GLA Angelica root, and Coleusforskohlii.
 22. (Cancelled)
 23. (Cancelled)
 24. (Cancelled) 25.(Cancelled)